A Randomized, Double-blind, Sponsor Un-blinded, Placebo-controlled, Phase 2a Crossover Study to Evaluate the Effect of the TRPV4 Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo)
研究概览
简要总结
This study is a single centre, randomised, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 crossover study in adults with heart failure. In blocking the TRPV4 ion channel and reducing pulmonary interstitial fluid, GSK2798745 may improve pulmonary function, respiration, and gas exchange as well as sleep-disordered breathing in patients with heart failure. Therefore, the current study is designed to investigate the effect of repeat administration of GSK2798745 on pulmonary gas exchange and pulmonary function.
A sufficient number of subjects with heart failure will be enrolled so that 12 subjects complete the two study periods and critical assessments. Subjects will be randomised to receive either GSK2798745 or placebo once daily for a period of 7 days in one treatment period and alternate study medication in the second treatment period. Both the treatment periods will be separated by a washout period of at least 14-days.
This study will consist of a Screening visit within 14 days of the start of Period I and two treatment periods wherein eligible subjects will be randomised to one of the two treatment sequences, a follow-up visit approximately 2 weeks after the completion of second study period. The total duration of the study is approximately 8 weeks from screening to follow-up visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •>=21 years of age at the time of signing the informed consent form.
- •Diagnosis of heart failure (New York Heart Association Class II-IV) for a minimum of 3 months prior to screening.
- •Clinically stable with no changes in optimized guidance-directed medications and no hospitalizations for heart failure for at least 1 month prior to Screening.
- •N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) >1000 picogram per milliliter (pg/mL) measured within 6 months prior to OR at Screening.
- •Average DLco measurements outside the normal range (percent [%] predicted DLco < 80%) during the Screening Period.
- •Body mass index (BMI) >=18 and <=40 kilogram per meter square (kg/m^2).
- •Male or female of non-childbearing potential-
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
排除标准
- •History of acute coronary syndromes including unstable angina or myocardial infarction within 6 months of screening.
- •Coronary revascularization including angioplasty and stenting within 6 months of Screening.
- •History of stroke or seizure disorder within 5 years of Screening.
- •Diagnosis of asthma.
- •Diagnosis of chronic obstructive pulmonary disease (COPD) with FEV1 <50% of predicted measured within 4 weeks of Screening.
- •History of a condition that required radiation therapy to the thorax.
- •History of any type of malignancy within the past five years with the exception of successfully treated basal cell cancer of the skin.
- •Active ulcer disease or gastrointestinal bleeding.
- •Current or chronic history of liver disease, known hepatic impairment, or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Alanine transaminase (ALT) >2x Upper Limit of Normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- •QT interval corrected (QTc) > 450 millisecond (msec) or QTc > 480 msec in subjects with Bundle Branch Block.
- •History or current evidence of any serious or clinically significant gastrointestinal, renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on permitted therapies or that would, in the opinion of the investigator or the GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for inclusion in this study.
- •Use of medications specified for the treatment of COPD including short- and long acting bronchodilators (beta-agonists and anticholinergics) and inhaled glucocorticoids as well as oxygen therapy.
- •Use of a listed prohibited medication within the restricted timeframe relative to the first dose of study medication.
- •Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-glycoprotein.
- •Current smoker.
- •History of drug/substance abuse within the past 2 years.
- •History of alcohol abuse within 6 months of the study. Defined as an average weekly alcohol consumption of >14 drinks for men or >7 drinks for women. One drink is equivalent to 12 grams (g) of alcohol: approximately 12 ounces (360 milliliters [mL]) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces of (45 mL) 80 proof distilled spirits.
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
- •Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months of screening. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
- •A positive pre-study drug/alcohol screen.
- •Use of another investigational product in a clinical study within the following time period prior to the first administration of study medication in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Exposure to more than 4 investigational medicinal products within 12 months prior to the first administration of study medication.
研究组 & 干预措施
GSK2798745 and Placebo
Each subject will be randomized to receive GSK2798745 2.4 milligrams (mg) and Placebo once daily for 7 days, each in one of the two treatment periods. Two treatment periods will be separated by a 14-day washout period.
干预措施: GSK2798745 (Drug)
GSK2798745 and Placebo
Each subject will be randomized to receive GSK2798745 2.4 milligrams (mg) and Placebo once daily for 7 days, each in one of the two treatment periods. Two treatment periods will be separated by a 14-day washout period.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo)
时间窗: Baseline, Day 4, Day 5 and Day 7 of each treatment period
DLco is a measure of the ability of a gas to transfer from alveoli across the alveolar epithelium and capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. Data of DLco (milliliter per millimeter of mercury per minute \[mL/mmHg/min\]) for Mayo site is presented.
Change From Baseline in the Diffusing Capacity of the Lung for DLco on Pulmonary Gas Transfer (Site: Hennepin)
时间窗: Baseline, Day 4, Day 5 and Day 7 of each treatment period
DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to the symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 Pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Statistical analysis was not performed as the sample size was too small
次要结局
- Change From Baseline in Functional Residual Capacity (FRC)(Baseline, Day 4 and Day 7 of each treatment period)
- Change From Baseline in Diffusing Capacity of the Lung for Nitric Oxide (DLno) and Membrane Conductance (DM)(Baseline, Day 4, Day 5 and Day 7 of each treatment period)
- Change From Baseline in Capillary Blood Volume (Vc)(Baseline, Day 4, Day 5 and Day 7 of each treatment period)
- Change From Baseline in End-expiratory Lung Volume (EELV) Measured by Body Plethysmograph(Baseline, Day 4 and Day 7 of each treatment period)
- Number of Participants With Abnormal Electrocardiogram (ECG) Findings(Up to Day 7 in each treatment period)
- Change From Baseline in Creatinine, Direct Bilirubin, Total Bilirubin, Uric Acid(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in the Ventilation/Volume of Carbon Dioxide Production (VE/VCO2) Ratio(Baseline and Day 7 of each treatment period)
- Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Mayo)(Baseline, Day 5 and Day 7 of each treatment period)
- Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Hennepin)(Baseline, Day 5 and Day 7 of each treatment period)
- Change From Baseline in Systolic Blood Pressure(SBP) and Diastolic Blood Pressure (DBP)(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 Second (FEV1), Forced Expiratory Flows (FEF) 25-75, FEF50 and FEF75(Baseline, Day 4 and Day 7 of each treatment period)
- Respiratory Rate Over Time Continuously Measured by Body Sensor (Site: Mayo Only)(Up to Day 7 of each treatment period)
- Change From Baseline in Heart Rate(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Albumin and Total Protein Values(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Hematology: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, White Blood Cell (WBC) Count, Total Neutrophils(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Dyspnea Score(Baseline, Day 5 and Day 7 of each treatment period)
- Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase, Gamma Glutamyl Transferase (GGT) Values(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Respiration Rate(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Percent Oxygen in Blood(Baseline and up to Day 7 of each treatment period)
- Number of Participants With All Adverse Events (AE) and Serious Adverse Events (SAE)(Up to Day 46)
- Change From Baseline in Temperature(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Chemistry: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN)(Baseline and up to Day 7 of each treatment period)
- Change From Baseline in Digoxin Level(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Chemistry: N-terminal Pro-Brain Natriuretic Peptide(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Mean Corpuscle Hemoglobin(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Participant Reported Health Status (SF-36) Acute Score(Baseline and Day 7 of each treatment period)
- Time to Maximum Observed Plasma Concentration (Tmax) for GSK2798745(Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose))
- Elimination Half Life (T½) for GSK2798745(Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose))
- Change From Baseline in Troponin I Levels and Type I Collagen Cross-linked C-telopeptide(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Hematocrit(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Hemoglobin(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Mean Corpuscle Volume(Baseline and up to Day 7 in each treatment period)
- Change From Baseline in Red Blood Cell Count (RBC) and Reticulocytes(Baseline and up to Day 7 in each treatment period)
- Area Under the Concentration Time Curve (AUC) Time Zero to the Last Time of the Last Quantifiable Concentration (AUC(0-t)), AUC Over the Dosing Interval After First and Last Dose (AUC(0-tau)) and AUCall for GSK2798745(Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose))
- Maximum Drug Concentration (Cmax) for GSK2798745(Day 1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours post-dose), Day 2 (pre-dose, 12 hours post-dose), Days 3 to 6 (pre-dose), Day 7 (Pre-dose, 0.5, 1, 1.5, 2, 3, 5, 10, 24 and 48 hours post-dose))
- Change From Baseline in Mean Corpuscle Hemoglobin Concentration(Baseline and up to Day 7 in each treatment period)